Multiple mechanisms and multiple oxidants in P450-catalyzed hydroxylations

• Published in: Archives of Biochemistry and Biophysics Vol. 409; no. 1; pp. 72 - 79
• Main Authors: Newcomb, Martin, Hollenberg, Paul F, Coon, Minor J
• Format: Book Review Journal Article
• Language: English
• Published: United States Elsevier Inc 2003
• Subjects: Activated oxygen; Biochemical Phenomena; Biochemistry; Catalysis; Cations; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Free Radicals; Heme - chemistry; Hydroperoxo-iron; Hydroxylation mechanism; Iron-oxo; Mixed Function Oxygenases - metabolism; Models, Chemical; Oxygen - metabolism; Iron-oxo; Activated oxygen; Hydroxylation mechanism; Cytochrome P450; Hydroperoxo-iron
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/S0003-9861(02)00445-9

Cytochrome P450 enzymes catalyze a number of oxidations in nature including the difficult hydroxylations of unactivated positions in an alkyl group. The consensus view of the hydroxylation reaction 10 years ago was that a high valent iron-oxo species abstracts a hydrogen atom from the alkyl group to give a radical that subsequently displaces the hydroxy group from iron in a homolytic substitution reaction (hydrogen abstraction–oxygen rebound). More recent mechanistic studies, as summarized in this review, indicated that the cytochrome P450-catalyzed “hydroxylation reaction” is complex, involving multiple mechanisms and multiple oxidants. In addition to the iron-oxo species, another electrophilic oxidant apparently exists, either the hydroperoxo-iron intermediate that precedes iron-oxo or iron-complexed hydrogen peroxide formed by protonation of the hydroperoxo-iron species on the proximal oxygen. The other electrophilic oxidant appears to react by insertion of OH
+ into a C–H bond to give a protonated alcohol. Computational work has suggested that iron-oxo can react through multiple spin states, a low-spin ensemble that reacts by insertion of oxygen, and a high-spin ensemble that reacts by hydrogen atom abstraction to give a radical.